Production of Spinosad

Spinosad is produced directly from the fermentation of a strain of Saccharo-polyspora spinosa. Production strains of S. spinosa have been selected for increased titers of spinosyns A and D, however, no genetic engineering techniques have been used in this process and no genetically-modified organisms are used in the production process. After fermentation, the spinosyn A and D mixture is extracted from the fermentation broth, precipitated and dried to create technical spinosad, which is then formulated into end-use products. Spinosad technical material is also produced under pharmaceutical manufacturing guidelines to be used as a flea control agent in companion animals.

5.9.2 Production of Spinetoram

Production of spinetoram begins with the fermentation of a mutant strain of Saccharopolyspora spinosa that produces primarily spinosyns J and L, rather than spinosyns A and D. This strain was generated through mutagenesis of S. spinosa. However, like the spinosad-producing strains, no genetic engineering techniques were used in this process and no genetically-modified organisms are used in the production process. After fermentation, the spinosyn J and L mixture is extracted from the fermentation broth and precipitated in preparation for the two chemical synthesis steps required to produce spinetoram. The solvents used in extracting and precipitating the spinosyn J and L mixture are recycled.

Spinosyns J and L, unlike spinosyns A and D, have a free hydroxyl group at the 30-position on the rhamnose sugar, which allows for chemical manipulation of this site (see Figure 5.10). In the first synthetic step, the free hydroxyl at the 30-position in spinosyn J and spinosyn L is ethylated to yield a mixture of 30-O-ethyl spinosyn J and 30-O-ethyl spinosyn L. This material is then hydrogenated to yield a mixture of spinetoram-J (30-O-ethyl-5,6-dihydro spinosyn J; see Figure 5.2, structure 5.5) and spinetoram-L (30-O-ethyl spinosyn L; see Figure 5.2, structure 5.6). The hydrogenation conditions are selective and reduce only the disubstituted double bond between C5 and C6 in the 30-O-ethyl spinosyn J intermediate, leaving the 30-O-ethyl spinosyn L unchanged. The material is crystallized from the reaction mixture and dried to create technical spinetoram, which is then formulated into end-use products.

5.9.3 Formulation Attributes of the Spinosyns

To meet a variety of market needs, spinosad and spinetoram products span a very wide range of formulation types (see Table 5.8).

The range of possible formulations for any pesticide is determined by the physical and chemical properties of the active ingredient. Three primary properties determine the formulation characteristics of the spinosyns: (1) both

Spinosyn Insecticide
Figure 5.10 Chemical synthesis steps in spinetoram manufacturing.

Table 5.8 Spinosyn product formulation types and associated uses.

Formulation type

Use pattern

Suspension concentrate

Emulsifiable concentrate Wettable granule Wettable powder Dustable powder Sprayable bait Granular bait Bait stations Granules Tablets

Chewable tablets Gel, paste Creme rinse

Crops, ornamentals, forestry, stored grain, animal health, public health, turf, home and garden Public health Crops

Crops, ornamentals, seed treatment

Stored grain, crops

Crops

Crops, animal health, urban pests

Urban pests

Public health

Public health

Animal health

Urban pests

Public health are fermentation-derived mixtures; (2) both are weak bases; and (3) both have significant solubility in organic solvents.

As fermentation-derived products, spinosad and spinetoram are mixtures composed primarily of two similar, but not identical molecules. In terms of physical properties, a significant difference between the major and minor components of both spinosad and spinetoram is the presence or absence of a methyl group at C6 on the tetracycle (see Table 5.9). With regard to components of spinosad, spinosyn D (methyl group at C6) has a melting point 71 °C higher than that of spinosyn A (hydrogen at C6), and the water solubility of spinosyn D (at pH 7) is almost 1000-fold lower than that of spinosyn A. With regard to the components of spinetoram, spinetoram-L (methyl group at C6) has a melting point 72 °C lower than that of spinetoram-J (hydrogen at C6), and the water solubility of spinetoram-L (at pH 7) is four-fold higher than that of spinetoram-J. The melting points and water solubilities of the mixtures that constitute technical spinosad and technical spinetoram are determined by the relative ratios of the major and minor components.

The predominant components of both spinosad and spinetoram all have pKa values of about 8 (see Table 5.9). As a weak base, the solubility of spinosyns in water increases as the pH is reduced. From a formulation perspective, at pH level above 5, the spinosyns behave like high-melting solids with little water solubility, which results in the predominant agricultural formulations being suspension concentrates and wettable granule formulations composed of milled crystalline particles. Acid salts of spinosyns can be produced and are used in animal health formulations. The basic nature of the spinosyns is also a consideration when combining multiple active ingredients into the same formulation.

The spinosyns have significant solubility in organic solvents (see Table 5.9). This property is relatively rare in high-melting solids with limited water solubility, and has proven to be useful in a number of formulations for

Table 5.9 Selected physical properties of spinosyn A, spinosyn D, spinetoram-

J, and spinetoram-L.

Table 5.9 Selected physical properties of spinosyn A, spinosyn D, spinetoram-

J, and spinetoram-L.

Property

Spinosyn A133

Spinosyn D133

Spinetoram-J134

Spinetoram-L134

Melting point, °C

84-99.5a

161.6-170a

143.4b

70.8b

Water solubility,

235

0.332

11.3

46.7

mg/lc'd'e

pKaf

8.10e

7.87e

7.86g

7.59g

Solubility in organic solvents, mg/Lc

Acetone

168 000

10100

>250000

>250000

Ethyl acetate

194000

19 000

>250000

>250000

w-Heptane

12 400

300

23 900

>250000

Methanol

190000

2520

163 000

>250000

Xylene

> 250 000

64000

>250000

>250000

"Visual determination. bDiffential scanning calorimetry. cShake flask. ^Buffered to pH 7. eAt 20 °C.

fCapillary zone electrophoresis. gAt 25 °C.

"Visual determination. bDiffential scanning calorimetry. cShake flask. ^Buffered to pH 7. eAt 20 °C.

fCapillary zone electrophoresis. gAt 25 °C.

non-agricultural markets, such as mosquito control and animal health. It is also a consideration when combining the spinosyns with other active ingredients.

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